Unfamiliar to many rising and practicing radiologists, its impact is profound in the world of imaging for diagnosis and treatment planning.
By Ibrahim Rehman, 4th-year medical student at Indiana University School of Medicine
The summer after my first year of medical school, I joined a university-affiliated lab that produced many of the radiotracers used in PET imaging at the hospital. I returned in the summer of 2024 to work on the design and synthesis of new tracers not yet in clinical use. Across both stints, I got to witness a side of radiology that most students and many physicians never see — pulling back the curtain on the world of radiochemistry — a niche and essential discipline of modern imaging.
Atoms consist of a nucleus surrounded by electrons. Some atomic nuclei are so unstable that they release energy in the form of radiation to reach a more stable state. This process is known as radioactive decay, which often changes the composition of the nucleus. This results in the transformation of one element into another. Any substance capable of undergoing decay is considered radioactive.
Enter radiochemistry — the chemistry of radioactive compounds. The same chemistry behind building everyday organic compounds can also be applied to a variety of radioactive substances. One important class of these substances is radiotracers, compounds used to track or trace processes in the body. At minimum, radiotracers consist of two components:
Vectors may target specific receptors/proteins or mimic naturally occurring molecules to highlight processes in the body. Many vectors begin as precursors or non-radioactive molecules that serve as the starting materials in radiochemical reactions.
The same chemistry behind building everyday organic compounds can also be applied to a variety of radioactive substances.
Like other molecular compounds, radiotracers can be made using established chemical principles — the only difference being that your product in radiochemistry is actively decaying by the minute. Decay is an inevitable and unavoidable process when working with radioactive materials, but several strategies can help maximize yield.
One way is to design and use a suitable precursor. A good precursor should be stable enough to store, but reactive enough that radiochemistry can occur quickly. It should also be designed such that the final product can be synthesized in as few reaction steps as possible, minimizing both time and radioactive decay. Another approach to combat decay is to use a radioactive label (radioisotope) with a longer half-life. For example, Carbon-11 has been widely used in research, but its short half-life of 20 minutes can make production a race against time. Fluorine-18 on the other hand has a half-life of about 110 minutes, giving us more leeway when it comes to getting the tracer to its final destination. Finally, keeping the radiochemistry site close to the hospital and coordinating transport efficiently can help minimize time spent in transit from production to patient.
Another important consideration in radiochemistry is exposure to ionizing radiation. To protect users, all productions are conducted inside a hot cell, a massive lead-shielded box made to absorb radiation. Reactions and transfers are further automated using specialized programs, limiting direct handling of radioactive materials while ensuring standardized and reproducible results.
Making a radiotracer starts with the precursor. This typically involves brainstorming potential chemical structures and selecting the best option based on costs, ease of production and overall usefulness for synthesis. Next, we work backwards from the precursor to determine the necessary starting materials and the number of reaction steps involved in the synthetic route. Using what we know from organic chemistry, the precursor can then be synthesized based on our planned scheme.
With the precursor ready, the radiochemistry phase begins. First, we program the sequence of necessary reactions and transfer steps for automation. Then, we use a special type of particle accelerator known as a cyclotron to generate the Fluorine-18 radioisotope. After the automation is finished, the precursor should be radiolabeled, usually via a substitution reaction that swaps out part of the molecule with Fluorine-18. However, the reaction mixture still needs to be purified so that the radiotracer is safe and effective for use. For purification, we typically rely on high-performance liquid chromatography (HPLC) given its ability to quickly and precisely separate compounds. With HPLC, we can eliminate impurities and contaminants from the reaction mixture and finally isolate the product.
To verify the chemical identity of the tracer, a small sample is submitted for HPLC analysis and compared to a cold standard (or a non-radioactive version of the product) for reference. After the product is successfully characterized and deemed suitable for injection, it is stored in a lead case and given to a designated driver for transport to the hospital.
Radiochemistry may be unfamiliar to most budding and current radiologists, but its impact is profound in the world of imaging. By enabling radiotracers to pinpoint pathology at the molecular level, it has already changed diagnosis and treatment planning for several diseases, including prostate cancer and neuroendocrine tumors. As the landscape of radiology evolves and shifts toward molecular imaging, radiochemistry will remain a critical player in shaping how we detect and treat diseases.
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